What is the effect of Acetaminophen (Paracetamol)?

From the Guidelines

Acetaminophen is recommended at a daily dose of 2-3 g for patients with liver cirrhosis, as it is generally safe and unlikely to cause clinically significant hepatotoxicity at this dose. When considering pain management, it's essential to weigh the risks and benefits of different analgesics. According to the 2022 klca-ncc korea practice guidelines for the management of hepatocellular carcinoma 1, acetaminophen is a suitable option for mild pain, with amounts of less than 4 g per day being very unlikely to cause clinically significant hepatotoxicity. However, it's crucial to limit the dose of acetaminophen to ≤325 mg per dosage unit when combined with other analgesics as a fixed dose combination.

Some key points to consider when prescribing acetaminophen include:

• The half-life of acetaminophen is increased several folds in patients with liver cirrhosis compared to healthy individuals 1
• A daily dose of 2-3 g of acetaminophen has been reported to have no association with decompensation in patients with liver cirrhosis 1
• Patients with liver cirrhosis are at risk of metabolic disorder and prolonged half-life of acetaminophen, making a daily dose of 2-3 g a generally recommended limit 1
• NSAIDs, on the other hand, have a higher concentration of free compounds in patients with liver disease and are more likely to cause side effects and toxicity, making them a less desirable option 1

In terms of dosing, the standard adult dose of acetaminophen is 325-650 mg every 4-6 hours as needed, not exceeding 3,000 mg in 24 hours. For children, dosing is weight-based, typically 10-15 mg per kilogram of body weight every 4-6 hours. It's essential to always check labels to avoid accidental overdose, especially when acetaminophen is found in combination cold and flu medications. If pain persists beyond a few days or if fever lasts more than three days, medical attention should be sought.

From the FDA Drug Label

WARNINGS Liver warning: This product contains acetaminophen. Severe Liver damage may occur if you take • more than 6 caplets in 24 hours, which is the maximum daily amount • with other drugs containing acetaminophen • 3 or more alcoholic drinks everyday while using this product Do not use • with any other drugs containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist. • if you are allergic to acetaminophen or any of the inactive ingredients in this product.

The main warnings for acetaminophen are:

• Liver damage if taken in excess or with other acetaminophen-containing products
• Allergic reactions, including severe skin reactions
• Contraindications for use with other acetaminophen-containing products or in patients allergic to acetaminophen 2 2

From the Research

Acetaminophen Overview

• Acetaminophen has been widely used for over 50 years in the treatment of pain and fever, providing safe and effective relief of these symptoms 3.
• It is one of the most popular and safe pain medications worldwide, but can cause severe liver injury and even acute liver failure (ALF) due to intentional or unintentional overdoses 4.

Acetaminophen Toxicity

• Acetaminophen toxicity is the most common cause of acute hepatic failure in the United States, accounting for approximately 50 percent of all reported cases and 20 percent of liver transplants 5.
• In 2021, poison control received more than 80,000 cases involving acetaminophen-containing products, and acetaminophen toxicity is responsible for 56,000 - 75,000 emergency department visits annually 5.
• The introduction of acetaminophen combination products has compounded the issue, with unintentional and chronic overdose accounting for over 50 percent of cases of acetaminophen-related acute hepatic failure in the United States and United Kingdom 5.

Mechanisms of Acetaminophen-Induced Cell Death

• The formation of a reactive metabolite is responsible for hepatic glutathione depletion and initiation of the toxicity 4.
• Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria 4.
• The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown, leading to cell death 4.

Clinical Presentation and Outcomes

• Patients taking APAP with opioids were older, had more comorbidities, and were more likely to have unintentional overdose 6.
• On presentation, 58% in the APAP/opioid group had advanced encephalopathy as compared with 43% with APAP alone 6.
• No significant differences were observed in clinical outcomes among the groups, including delayed hepatotoxicity or clinical outcomes 6.